Breast cancer is the most common cancer in women and predominantly affects older women. Combined hormone therapy (CHT) is a risk factor for breast cancer and is the dominant source of exogenous progesterone and estrogen for post-menopausal women. We postulate that a key mechanism by which exogenous progesterone may influence carcinogenesis is through its proliferative effect on cells via the progesterone receptor B (PRB) and the differential metabolism of exogenous progesterone affecting the availability of progesterone to bind to the receptor. To test this hypothesis, we propose to genotype functional single nucleotide polymorphisms (SNPs) and tagSNPs in the PGR gene, and the following progesterone metabolizing genes, AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2, and the CYP3A4 gene. We will investigate whether variation in these genes alters the risk of breast cancer overall and modifies the risk of breast cancer in relation to CHT use. No prior study has targeted this combination of genes involved in the progesterone mediating pathway, using the more comprehensive tagSNPs approach. Recent evidence suggests that the effects of hormone-mediated factors like CHT differ according to histologic type and hormone receptor status. Thus, subset analyses will be performed in relation to the risk of ER+/PR+ tumors and lobular tumors. This study of 1,299 women with invasive breast cancer and 1,063 controls will be conducted on the foundation of two population-based case-control studies of breast cancer conducted in the Seattle metropolitan area. This study is highly efficient due to the previous collection of exposure data and DNA samples. The comprehensive tagSNP and haplotype-based approach employed by this study to evaluate genes in the progesterone mediating pathway for association with breast cancer risk, and particularly in relation to the deleterious effect of CHT on breast cancer, in a population-based setting offers an optimal and unprecedented strategy for testing this hypothesis. By investigating the mechanism by which exogenous progesterone impacts breast cancer risk, this study offers the potential to enhance our abilities to prevent breast cancer, develop novel anti-cancer therapies, and improve risk assessment.